The brain-enriched tyrosine phosphatase STEP is emerging as a novel target for modulating neurological disorders related to excitotoxicity, including stroke. STEP is expressed in neurons of the cortex, hippocampus, and striatum, and participates in neuronal cell survival following an excitotoxic insult. The neurotransmitter glutamate plays a critical role in regulating the activity of STEP and our recent studies indicate that rapid activation of endogenous STEP can provide initial neuroprotection against ischemic injury. However we found that degradation of the active STEP over time allows activation of deleterious ischemic cascades responsible for ischemic brain injury. Restoration of STEP signaling with intravenous administration of a stable STEP derived peptide (TAT-STEP-myc peptide) provides significant protection against ischemic brain injury measured at 24 hr. The long-term goal of our current research is to determine whether the STEP signaling pathway is a potential target for treatment of ischemic stroke and related neurological disorders. The objective of this particular application is to determine whether interventions to restore STEP signaling can facilitate long- term protection from ischemia-induced brain damage and improve functional recovery in both young and aging animals. The central hypothesis is that the STEP signaling pathway, through its concerted action on multiple deleterious cascades of ischemic injury can evolve as a unique and effective target for stroke therapy. The proposed study will use magnetic resonance imaging (MRI) and behavioral studies for longitudinal evaluation of ischemic brain injury and neurological outcome, and determine the therapeutic time window of protection. To understand the molecular mechanism(s) of neuroprotection, the study will delineate the deleterious cascades that are suppressed by STEP. Furthermore the study will investigate the mechanism(s) involved in age-dependent increase in oligomerization and subsequent inactivation of STEP. The study will also evaluate the ability of an oligomerization-resistant STEP peptide in reducing ischemic injury in aging animals. The development and use of novel, stable, brain-permeable and degradation-resistant agent as well as the use of STEP KO mice and aging animals as tools to establish the neuroprotective potential of a tyrosine phosphates in ischemic brain injury is innovative. We rationalize that these studies will advance our understanding of the molecular mechanisms involved in the regulation of STEP and its function in both young and aging brain. The proposed research is significant since it will provide the first evidence for the role of a tyrosine phosphatase in limiting ischemic brain injury and may provide a much-needed target for therapeutic intervention in ischemic stroke.